The long term objective of this program is to develop the methods for using PET to measure biochemical, neurochemical and biological mechanisms of disease, providing emical markers for highly specific differential diagnosis and treatment. In one part of is objective, we focus our effort on a single neurochemical (dopaminergic) system to study its regulatory mechanisms at an ultrastructural level and develop in vivo probes and assay methods of the pre- and postsynaptic chemical processes that underlie neurotransmitter function. The validity and value of these methods will be assessed under altered states of pharmacologic and electrical stimulation, as well as MPTP induced degeneration. Initially, selected diseases of this system: Parkinsons and umans exposed to MPTP - (presynaptic); Huntington's disease (HD) - (postsynaptic); progressive supranuclear palsy - (pre- and postsynaptic) will be used as models of system failure. Subsequently, these studies will evolve into the use of the methods to study the mechanisms of these diseases and their treatment. Another approach will be to use combinant DNA markers to identify HD gene carriers, while using PET to isolate and follow disease progression in target sites of HD gene expression in the brain. Studies of the metabolic aspects of maturation provide a unique model to investigate structure/function relationships that occur during periods of neuronal plasticity, in normal development or during compensatory responses to injury. Metabolic, anatomical and behavioral studies will be used to assess promotion of compensatory responses (i.e., novel growth and sparing of neuronal processes) by physical and chemical stimuli. These studies will combine specific findings in humans and rigorous detailed investigations only possible in animals. Intractable childhood seizures, Down Syndrome and infantile hemiplegia will be used as model disorders to investigate the metabolic basis of altered development and neuronal plasticity, with improved clinical management with PET expected to be an early outcome. A 3-D system for merging structure (MRI) and function (PET) will provide a systematic, accurate and efficient way iiot only process and interpret imaging data, but also to provide a new way to organize, describe and display human macroscopic functional anatomy of the brain.